USPTO Patents Application 09889251

In the Application of PATENT
Robert K. Naviaux Attorney Docket No.: UCSD1 140-1

Application Serial No.: 09/889,251
Filed: November 1, 2001
Page 2

IN THE CLAIMS

Please enter claims 1, 3, 25, and 27 as rewritten below. The following listing of
claims replaces all prior listings.

1 . (Currently Amended) A method for the treatment of a disorder
comprising administering to a subject having or at risk of having such disorder an
effective amount of a compound of Formula I:

Ri

FUO

wherein:

Ri is ©, OH, NHCOCH3, or NH 2 ,
R 2 is H, C0 2 H, or

wherein:

each X is independently H or optionally substituted
C t -C 2 2 alkyl, optionally substituted C1-C22 alkenyl, or optionally
substituted C r C 22 alkynyl, with substituents selected from the
group consisting of H, C1-C3 alkyl, OH, NH 2 , and halogen,

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, In the Application of PATENT
Robert K. Naviaux Attorney Docket No.: UCSD1 140-1

Application Serial No.: 09/889,251
Filed: November 1,2001
Page 3

R 3 , R4, and R 5 are each independently optionally substituted Q-C22
alkyl carbonyl, with substituents selected from the group consisting of Ci-
C 3 alkyl, OH, NH 2 , and halogen, or H, wherein at least one of R 3 , R4, and

R 5 , are is not H, and
wherein the disorder is selected from renal tubular acidosis (RTA); Leigh
syndrome; MARIAHS syndrome; mitochondrial disease leading to stroke-like episodes;
lactic acidemia; Pyruvate Dehydrogenase (PDH) deficiency; encephalomyopathy; ataxia
and encephalopathy; cytochrome c oxidase (COX, Complex IV) deficiency;
cardiomyopathy; Alzheimer's disease; Complex I deficiency; multiple mitochondrial
deletion syndrome, and any combination thereof, thereby treating the disorder.

2. (Previously amended) The method of claim 1 wherein, the compound is 2\3',5'-
tri-0-acetyl-l-P-D-uridine.

3. (Currently amended) The method of claim 1, wherein the optionally substituted
alkyl carbonyl is unbranched and has is in the range of about 5 to 22 carbons.

4. (Previously amended) The method of claim 1, wherein the alkyl carbonyl is a
carbonyl moiety of an amino acid selected from the group consisting of glycine, L- forms
of alanine, valine, leucine, isoleucine, tyrosine, proline, hydroxyproline, serine, threonine,
cystine, cysteine, aspartic acid, glutamic acid, arginine, lysine, histidine, carnitine, and
ornithine.

5. (Previously amended) The method of claim 1, wherein the alkyl carbonyl is a
carbonyl moiety of a dicarboxylic acid having in the range of about 3 to 22 carbons.

6. (Previously amended) A method according to claim 1, wherein the disorder is a
primary disorder comprising at least one mutation in mitochondrial or nuclear DNA.

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In the Application of
Robert K. Naviaux
Application Serial No.: 09/889,251
Filed: November 1, 2001
Page 4

7. (Canceled)

8. (Previously amended) The method of claim 1, wherein the disorder is a deficiency
of cardiolipin.

9. (Previously amended) The method of claim 1, wherein the disorder comprises a
deficiency in a pyrimidine synthetic pathway.

1 0. (Previously amended) The method of claim 9, wherein the deficiency in a
pyrimidine synthetic pathway is the uridine synthetic pathway.

1 1 . (Previously amended) The method of claim 9, wherein the deficiency comprises
reduced expression and/or activity of an enzyme in the pyrimidine synthetic pathway.

12. (Previously amended) The method of claim 1 1, wherein the enzyme is selected
from the group consisting of dihydroorotate dehydrogenase (DHOD) and uridine
monophosphate synthetase (UMPS). •

13. (Previously amended) The method of claim 1, wherein the disorder results in
lower than normal uridine levels.

14. (Previously amended) The method of claim 1, wherein the disorder is the result
of prior or concurrent administration of a pharmaceutical agent.

15. (Previously amended) The method of claim 14, wherein the pharmaceutical agent
is a reverse transcriptase inhibitor, a protease inhibitor or an inhibitor of DHOD.

16. (Previously amended) The method of claim 15, wherein the reverse transcriptase
inhibitor is Azidothymidine (AZT), Stavudine (D4T), Zalcitabine (ddC), Didanosine
(DDI) or Fluoroiodoarauracil (FIAU).

17. (Previously amended) The method of claim 15, wherein the protease inhibitor is
Ritonavir, Indinavir, Saquinavir or Nelfinavir.

PATENT

Attorney Docket No.: UCSD1 140-1

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In the Application of
Robert K. Naviaux

PATENT

Attorney Docket No.: UCSD1 140-1

Application Serial No.: 09/889,251
Filed: November 1,2001
Page 5

18. (Previously amended) The method of claim 14, wherein the DHOD inhibitor is
Leflunomide or Brequinar.

19. (Previously amended) The method of claim 1, further comprising the
administration of one or more co-factors, vitamins, or mixtures of two or more thereof.

20. (Previously amended) A method according to claim 19, wherein the co-factor is
one or both of Coenzyme Q10 or calcium pyruvate.

2 1 . (Previously Amended) A method according to claim 19, wherein the vitamin is
selected from the group consisting of thiamine (Bl), riboflavin (B2), niacin (B3),
pyridoxine (B6), folate, cyanocobalamine (B12), biotin, a-lipoic acid, and pantothenic
acid.

22. (Original) A method according to claim 1, wherein the compound of Formula (I)

2 2

is administered in a daily dosage in the range of about 0.5 g/m to 20 g/m .

23. (Original) A method according to claim 1, wherein the compound of Formula(I) is

2 2

administered in a daily dosage in the range of about 2 g/m to 10 g/m .

24. (Original) A method according to claim 1, wherein the compound of Formula(I) is
administered in a daily dosage of about 6.0 g/m 2 .

25. (Currently amended) A method for reducing or eliminating one or more
symptoms associated with a disorder comprising administering to a subject in need
thereof an effective amount of a compound of Formula I:

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In the Application of
Robert K. Naviaux
Application Serial No.: 09/889,251
Filed: November 1,2001
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OR 4 OR 3
(I)

wherein:

R x is 0, OH, NHCOCH3, or NH 2 ,
R 2 is H, C0 2 H, or

0

— co-{cxAcx3

wherein:

each X is independently H or optionally substituted
C1-C22 alkyl, optionally substituted C1-C22 alkenyl, or optionally
substituted Ci-C 22 alkynyl, with substituents selected from the
group consisting of H, C1-C3 alkyl, OH, NH 2 , and halogen,

R 3 , R4, and R 5 are each independently optionally substituted C1-C22
alkyl carbonyl, with substituents selected from the group
consisting of C1-C3 alkyl, OH, NH 2 , and halogen, or H, wherein at
least one of R 3 , R 4 , and R 5 , are is not H, wherein the disorder is selected from the group
consisting of renal tubular acidosis (RTA); Leigh syndrome; MARIAHS syndrome;
mitochondrial disease leading to stroke-like episodes; lactic acidemia; Pyruvate
Dehydrogenase (PDH) deficiency; encephalomyopathy; ataxia and encephalopathy;
cytochrome c oxidase (COX, Complex IV) deficiency; cardiomyopathy; Alzheimer's

PATENT

Attorney Docket No.: UCSD1 140-1

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In the Application of
Robert K. Naviaux

PATENT

Attorney Docket No.: UCSD1 140-1

Application Serial No.: 09/889,251
Filed: November 1, 2001
Page 7

disease; Complex I deficiency; multiple mitochondrial deletion syndrome, and any
combination thereof, thereby treating the disorder.

26. (Previously amended) A method for reducing or eliminating one or more
symptoms associated with a disorder of claim 1 comprising administering to a subject
having or at risk of having such disorder, an effective amount of triacetyluridine.

27. (Currently amended) A method according to claim 25 and claim 26, wherein said
symptoms are r e nal tubular acido s i s (RTA), impaired eyesight, dementia, seizures,
cardiomyopathy, skeletal myopathy, peripheral myopathy or autonomic myopathy.

28. (Canceled)

29. (Withdrawn) A method for treating or preventing pathophysiological
consequences of mitochondrial respiratory chain dysfunction in a mammal comprising
administering to said mammal in need of such treatment or prevention an effective
amount of a pyrimidine nucleoside.

30. (Withdrawn) A method as in claim 29 wherein said respiratory chain dysfunction
is caused by a mutation, deletion, or rearrangement of mitochondrial DNA.

3 1 . (Withdrawn) A method as in claim 29 wherein said respiratory chain dysfunction
is a deficit in mitochondrial Complex I activity.

32. (Withdrawn) A method as in claim 29 wherein said respiratory chain dysfunction
is a deficit in mitochondrial Complex II activity.

33. (Withdrawn) A method as in claim 29 wherein said respiratory chain dysfunction
is a deficit in mitochondrial Complex III activity.

34. (Withdrawn) A method as in claim 29 wherein said respiratory chain dysfunction
is a deficit in mitochondrial Complex IV activity.

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In the Application of PATENT
Robert K. .Naviaux Attorney Docket No.: UCSD1 140-1

Application Serial No.: 09/889,251
Filed: November 1, 2001
Page 8

35. (Withdrawn) A method as in claim 29 wherein said respiratory chain dysfunction
is a deficit in mitochondrial Complex V activity.

36. (Withdrawn) A method as in claim 29 wherein said pyrimidine nucleotide is
administered orally.

37. (Withdrawn) A method as in claim 29 wherein said pathophysiological
consequence of mitochondrial respiratory chain dysfunction is a congenital mitochondrial
disease.

38. (Withdrawn) A method as in claim 37 wherein said congenital mitochondrial
disease is selected from the group consisting of MELAS, LHON, MERRF, MNGIE,
NARP, PEO, Leigh's Disease, Alpers syndrome, mitochondrial cytopathy, mitochondrial
myopathy, mitochondrial encephalomyopathies, and Kearas-Sayre Syndrome.

39. (Withdrawn) A method as in claim 29 wherein said pathophysiological
consequence of mitochondrial respiratory chain dysfunction is a neurodegenerative
disease.

40. (Withdrawn) A method as in claim 39 wherein said neurodegenerative disorder is
Alzheimer's Disease.

41 . (Withdrawn) A method as in claim 39 wherein said neurodegenerative disorder is
Parkinson's disease.

42. (Withdrawn) A method as in claim 39 wherein said neurodegenerative disorder is
Huntington's Disease.

43. (Withdrawn) A method as in claim 29 wherein said pathophysiological
consequence of mitochondrial respiratory chain dysfunction is selected from the group
consisting of renal tubular acidosis, dilating or hypertrophic cardiomyopathy,
steatohepatitis, hepatic failure, and lactic acidemia.

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In the Application of
Robert K..Naviaux

PATENT

Attorney Docket No.: UCSD1 140-1

Application Serial No.: 09/889,251
Filed: November 1, 2001
Page 9

44. (Withdrawn) A method for treating developmental delay in cognitive, motor,
language, executive function, or social skills in a mammal comprising administration of
an effective amount of a pyrimidine nucleoside,

45. (Withdrawn) A method as in claim 44 wherein said developmental delay is a
subset of Attention Deficit/Hyperactivity Disorder.

46. (Withdrawn) A method as in claim 44 wherein said developmental delay is a
subset of autism associated with mitochondrial dysfunction.

47-53'. (Canceled)

54. (Withdrawn) A method as in claim 29 wherein said pyrimidine nucleoside is
selected from the group consisting of uridine, cytidine, an acyl derivative of uridine, an
acyl derivative of cytidine, orotic acid, an alcohol ester of orotic acid, or a
pharmaceutically acceptable salt thereof.

55. (Withdrawn) A method as in claim 54 wherein said pyrimidine nucleoside is
administered orally.

56. (Withdrawn) A method as in claim, 29 wherein said pathophysiological
consequence of mitochondrial respiratory chain dysfunction is a congenital mitochondrial

disease.

57. (Withdrawn) A method as in claim 56 wherein said congenital mitochondrial
disease is selected from the group consisting of MELAS, LHON, MERRF, NARP, PEO,
Leigh's Disease, Alpers syndrome, and Kearns-Sayre Syndrome.

58-61. (Canceled)

62. (Withdrawn) A method as in claim 29 wherein said pathophysiological
consequence of mitochondrial respiratory chain dysfunction is selected from the group

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In the Application of
Robert K..Naviaux

PATENT

Attorney Docket No.: UCSD1 140-1

Application Serial No. : 09/889,25 1
Filed: November 1, 2001
Page 10

consisting of renal tubular acidosis, dilating or hypertrophic cardiomyopathy,
steatohepatitis, hepatic failure, and lactic acidemia.

63-65. (Canceled)

66. (Previously amended) A method according to claim 1, wherein said disorder is a
secondary disorder caused by acquired somatic mutations, physiologic effects of drugs,
viruses, or environmental toxins that inhibit mitochondrial function.

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